Project Summary Siblings resemble each other more than expected based on the genes that they inherit from their parents. This unexpected finding derives from recent studies that measure the association between genotype (variations in DNA sequence) and traits (e.g. height or disease risk) among large populations of unrelated people. This discrepancy indicates that parents may transmit extra, non-gene, information to their offspring. This non-gene information is called epigenetics, literally ?beyond? genetics, and is a well-established field, but convention accepts that epigenetic information is erased each generation. Studies in the emerging field of transgenerational epigenetic inheritance (TEI) are challenging this convention. However, little is known about how inherited epigenetic information is encoded, how it responds to environmental conditions, and how it is transmitted between generations. Because inherited epigenetic information is malleable and may account for up to half the inheritance of disease risk, the answers to these questions will have an enormous impact on society and medicine. Investigating how TEI is established, maintained, and transmitted is challenging: it requires analysis of multiple generations and studies to date indicate that its effects are impermanent, fading with successive generations. The proposed research uses the nematode C. elegans to investigate TEI. C. elegans has numerous experimental advantages for studying TEI, primary among them is a fast, three-day, generation time and a powerful molecular tool called RNA interference (RNAi), which can direct the silencing of any gene. One special characteristic of RNAi in C. elegans is that the silencing signals, a form of RNA, can move between cells and tissues, including to the germline, thus transmitting silencing to future generations. Published studies from the applicants group characterized an RNAi-dependent mechanism of TEI, showing that epigenetic silencing could be maintained for nearly 20 generations. To further explore the transmission of TEI in C. elegans the applicant proposes (Aim 1) to investigate the activity and selectivity of proteins that transport RNA between cells; (Aim 2) to characterize the biogenesis and transport of endogenous mobile RNAs and to investigate their role in epigenetic inheritance; and (Aim 3) to investigate the prevalence, mechanisms, and utility of TEI for organismal adaption to environmental change.